Process for preparing 21-chloro-17-acyloxy-20-ketosteroids

ABSTRACT

21-CHLORO - 17 - ACKYLOXY - 20-KETOSTERIODS, ARE PREPARED FROM THE CORRESPONNDING 17,21-DIHYDROXY-20-KETOSTERIOD, CYCLIC 17,21-ORTHOESTERS IN A SINGLE STEP PROCESS WHICH COMPRISES THE REACTION OF A 17,21-DIHYDROXY-20-KETOSTERIOD, CYCLIC 17,21-ORTHOESTER WITH TRIPHENYLMETHKYL CHLORIDE.

United State w ABSTRACT OF THE DISCLOSURE 21-Chloro 17 acyloxy20-ketosteroids, are prepared from the corresponding17,21-dihydroxy-20-ketosteroid, cyclic 17,21-orthoesters in a singlestep process which comprises the reaction of a17,21-dihydroxy-20-ketosteroid, cyclic 17,21-orthoester withtriphenylmethyl chloride.

BRIEF DESCRIPTION OF THE INVENTION A 17,21-dihydroxy-20-ketopregnene,cyclic 17,21-orthoester may be reacted with triphenylmethyl chloride toyield the corresponding 21-chloro-17-acyloxy-20-ketopregnene. The A andthe A -pregnenes are specifically contemplated. Pregnenes having theformula CHaCl are preferred. In formula I, and throughout thespecification, the symbols have the following meanings:

Y is hydroxy, chlorine, or fluorine:

Z is hydrogen or halogen (halogen being defined as F, Cl, Br and II)when Y is hydroxy, and Z is chlorine when Y is chlorine or fluorine;

R is alkyl of 1 to 8 carbon atoms; and

R is hydrogen, a-methyl, p-methyl, u-acyloxy of the formula wherein R isalkyl of 1 to 8 carbon atoms, a-alkoxy of the formula R O wherein R isalkyl or phenylalkyl (alkyl being defined as alkyl of 1 to 8 carbonatoms).

The usual routes for the preparation of 21-chloro-l7- acyloxypregnenesutilize the corresponding 17,21-dihydroxypregnencs as startingmaterials. In one route, the 17,21-dihydroxypregnene is converted to its21-sulfonate derivative which is reacted with an inorganic chloride togive the 2l-chloro-l7-hydroxypregnene. The 17-hydroxyl group is thenselectively acylated (acylation at the 115- hydroxyl group or at the3-ketone function may occur) to give the 2l-chl0r0-17-acyloxypregnene.Alternatively, the 17,2l-dihydroxypregnene is converted to thecorresponding 17,21-cyclic orthoester which is then selectivelyhydrolyzed to the 17-ester. The 21-hydroxyl group is converted to the21-chlor0 derivative via the 21-sulfonate as before. Each of theseroutes involves a selective reaction which can prove difficult and alsorequires three or four steps.

DETAILED DESCRIPTION OF THE INVENTION It has been found that17,2l-dihydroxy-ZO-ketopregnene, cyclic 17,21-orthoesters may beconverted to 21- chloro-17-acyloxy-20-ketopregnenes, by reaction withtriphenylmethyl chloride. The reaction is run in an organic solvent,e.g., a halogenated hydrocarbon such as dichloromethane or chloroform atthe reflux temperature of the solvent, e.g., a halogenated hydrocarbonsuch as dichloro time ranging from 30 minutes to 4 hours, preferably forabout 1 to 2 hours. The reaction is preferably run in an inertatmosphere (e.g., nitrogen or argon).

The 17,21-dihydroxy-20-ketopregnene, cyclic 17,21- orthoesters which areused in the process of this invention are obtained from thecorresponding 17,2l-dihydrOXy-ZO-ketopregnenes by reaction with atrialkylorthoester. The reaction is run in a polar organic solvent,e.g., dimethylformamide or dimethylsulfoxide, at a temperature of fromC. to 160 C., preferably C. to C., for a period of time ranging from 2hours to 48 hours, preferably 4 hours to 24 hours. The reaction is runin an inert atmosphere, e.g., nitrogen or argon, in the presence of anacid catalyst, e.g., p-toluenesulfonic acid. Thus, in order to obtain a17,21-dihydroxy-20-ketopregnene, cyclic 17,21-orthoester which may beconverted to the preferred 2l-chloro-pregnenes of formula I, it isnecessary to react a steroid of the formula II CH2 OH with atrialkylorthoester of the formula III wherein R is alkyl of 1 to 4carbon atoms. The 17,21- dihydroxy-20-ketopregnene, cyclic17,21-orthoesters obtained have the formula:

21-Chlor0-9-fluora-1 15,1 7-dihydroxypregn-4-ene-3,20-

- dione, 1 7-valerate 9- Fluor0-1 1BJ 7,21 trihydroxypregn-4-ene-3,20-di0ne, cyclic 17,21-methylorthovalerate A solution of 5 g. of9-fiuoro-l1,6,17,21-trihydroxypregn'-4-ene-3,20-dione in 10 ml. each ofdimethylformamide and trimethylorthovalerate is heated at 125 C. under ablanket of nitrogen for hours with 50 mg. of p-toluenesulfonic acid. Thesolution is cooled, 0.2 ml. of pyridine added, and the solution pouredinto water and extracted with chloroform. The chloroform solution is 5washed with water, dried, and evaporated in -.vacu0 and the residuecrystallized from acetone-hexane to give 3.0 g. of9-fluoro-l1,8,l7,2l-trihydroxypregn-4-ene-3,20-dione, cyclic17,2l-methylorthovalerate, melting point 172 C.- 175 C.

(b) 21-Chloro-9-fluoro-1 1p,17-dihydroxy re n-4-ene-3.20-

dione, l7-valerate chloro 9 fluoro 1119,17 dihydroxypregn-4-ene-3,20-

dione, 17-valerate, melting point 209 C.21l C.

EXAMPLE 2 21-Chlor0-9-fluoro-11flJ7-dihydroxy-16a-methoxypregn- 34-ene-3,20-ai0ne, 17-acemte (a)9-Fluoro-l6a-methoxy-115,17,21-trihydroxypregn-4- cue-3,20-dione, cyclic17,21-ethylorthoacetate A mixture of 0.48 g. of 9-fluoro-16a-methoxy-11617, 21 trihydroxypregn 4 ene-3,20-dione, 10 mg. of p-toluenesulfonicacid, 1 ml. of triethylorthoacetate and 1 ml. of dimethylformamide isheated at 120 C. under a blanket of nitrogen for 15 hours. The solutionis cooled, 0.1 ml. of pyridine added, and the solution poured into 100ml. of water and extracted with chloroform. The chloroform solution iswashed with water, dried, and evaporated in vacuo to give an oil whichis purified by column chromatography over neutral alumina. Elution with4:1 chloroform-hexane gives 301 mg. of 9-fluoro-16a-mer thoxy-l1c,17,21-trihydroxypregn-4-ene-3,20-dione, cyclic17,21-ethylorthoacetate.

(b) 21-Chloro-9-fluoro-11p,17-dihydroxy-16a-methoxypregn-4-ene-3,20-dione, l7-acetate go Asolution of 300 mg. each of 9-fluoro-l6a-methoxy- 11fl,17,21trihydroxypregn-4-ene-3,20-dione, cycle 17, 21-ethylorthoacetate in 5ml. of dichloromethane is refluxed for 1 hour, cooled, and applied to a10 g. silica gel column. Elution with dichloromethane-chloroform gives94 mg. of21-chloro-9-fluoro-l1fl,17-dihydroxy-l6amethoxypregn-4-ene-3,20-dione,17-acetate, melting point 245 C.248" C., dec., when recrystallized fromacetonehexane.

EXAMPLE 3 4 trihydroxypregna-1,4-diene-3,2O -dione, 16,17 diacetatemelting point 296 C.298 C. dec.

Anal.

Calcd. for C H ClFO C, 60.42; H, 6.09; Cl, 7.14;

Found: C, 60.40; H, 5.87; Cl, 7.43; F, 3.71.

EXAMPLE 4 2I-Chl0r0-9-fluoro-1 1,9,1 6 a,1 7-trihydroxypregna-1,4-diene-3,20-di0ne, I6-acetate, 17-pr0pi0nate A solution of 3.2 g. of9-fluoro-l1/3,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, cyclic17,2l-ethylorthopropionate, 16-acetatc and 1.9 g. oftriphenyhnethylchloride in 25 ml. of dichloromethane is refluxed undernitrogen for minutes, cooled, and stirred at room temperature for 68hours. The resulting solution is chromatographed on a g.-alumino(neutral-activity II) col- 5-'. umn. Elution with dichloromethane gives2.2 g. of impure product which is chromatographed on an 80 g.-silica gelcolumn. Elution with chloroform gives 1.4 g. of TLC pure product. Tworecrystallizations from acetone-hexane gives 750 mg. of2l-chloro-9-fluoro-11fi,16a,17-trihyclroxypregna 1,4-diene-3,20-dione,16-acetate, 17 propionate melting point 285 C.287 C.

Anal.

Calcd. for C H ClFO C, 61.11; H, 6.31; CI, 6.94;

F, 3.72 Found: C, 61.37; H, 6.47; Cl, 6.84; F, 3.71.

EXAMPLES 5-8 Following the procedure of Example 3 but substituting the17,21-dihydroxy-20-ketopregnene, cyclic 17,2l-orthoester of Column 1 for9-fluoro-113,16a,17,21-tetrahydroxypregna 1,4 diene 3,20 dione, cyclic17,21-ethylorthoacetate, l6-acetate, the21-chloro-17-hydroxy-20-ketopregnene, 17-ester of Column II is obtained.

Example Column I Column II ltja-methylpregna-L4-hydroxy-lfia-methylpregnadiene-3,20-d1one, cyclic 1,4-diene-3,20dione,17- 17,21-ethyl orthoacetate. acetate.

6. 9-flu or0-16a-ethoxy-1l/8,17,2l- 2l-chloro-9-fiuoro-l16,17-(11-trlhydroxypregna-IA: y oxy-16a-ethoxypregna d1ene-3,20-d10ne, cyclic1,4-diene-3,20-dione, 17- 17,2l-ethyl orthoacetate. acetate.

7 9,1lfi-dlchloro-l7,21-dihy-9,115,21-trichloro-l7-hydroxydroxypregna-l,4.-dienepregna-1,4-diene-3,20-diol1e, 3,20-dione, cychc 17,21-17-propionate. ethyl orthopropionate.

8 9-fluoro-11,3,17,21-trihydroxy- 21-chloro-9-fluoro11B,l7-di-16B-rnethylpregna-L4- hydroxy-lfiB-methylpregnadiene-3,20-dione, cyclic1,4diene3,20-dione, 17- 17,21 ethyl orthopropionate. propionate.

What is claimed is:

1. A process for preparing a 21-chloro-17-acyloxy-20- ketopregnene froma 17,2l-dihydroxy-20-ketopregnene, cyclic 17,21-orthoester whichcomprises reacting a 17,21- dihydroxy-ZO-ketopregnene, cyclic17,2l-orthoester with triphenylmethyl chloride in an organic solvent atthe reflux temperature of the solvent.

2. A process in accordance with claim 1 wherein the17,21-dihydroxy-20-ketopregnenc, cyclic 17,2l-orthoester has the formulawherein Y is hydroxy, chlorine, or fluorine; Z is hydrogen or halogenwhen Y is hydroxy, and Z is chlorine when 5 6 Y is chlorine or fluorine;R is alkyl of 1 to 8 carbon 17,2l-dihydroxy-ZO ketopregnene, cyclic17,21-orthoester atoms; R is hydrogen, a-methyl, fi-methyl, u-acyloxy ofhas the formula the formula r-O\ R5 H 6:0 0/ R3CO- 5 wherein R is alkylof l to 8 carbon atoms, a-alkoxy of Y R2 the formula R O where in R isalkyl or phenyl-alkyl; and R is alkyl of l to 4 carbon atoms.

3. A process in accordance with claim 2 wherein the 1017,2l-dihydroxy-ZO-ketopregnene, cyclic 17,2l-orthoester has the formula5. A process in accordance with claim 2 wherein the 0:0 0 organicsolvent is a halogenated hydrocarbon. |....r

l References Cited Newman et al., J.A.C.S. 95, p. 278 (1973).

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 4. A process inaccordance with claim 2 wherein the 260239'55 D Notice of AdverseDecision in Interference In Interference No. 99,170, involving PatentNo. 3,832,366, C. M. Cimarusti, PROCESS FOR PREPARING 21-CHLORO-17-ACYLOXY-20-KETO- STEROIDS, final judgment adverse to the patentee wasrendered July 2, 1976, as to claims 1, 2, 1 and 5.

[Ofiicz'al Gazette N Member 30, 1.976.]

UNITED STATES PA'I'I'IN'I OFFICE K538 CERTIFICATE OF CORRECTION PatentNo. 832 366 Dat d August 27, 1974 Inventor(s) pher M. cimarustl It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 2, please insert the following between line 5 and line 6:

- methane or chloroform at the reflux temperature of the solvent. Thereaction mixtur'e'is refluxed for a period of Signed and sealed this29th day of October 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner ofPatents FORM po'wso (1059) USCOMM-DC wan-Poo I "is. GOVERNMINT PRINTINGOFFICE! I." 0-35633l

